The primary aim of this project is to increase our understanding of the role of the serotonergic neurotransmitter system in behavior. Animal model studies described in this project are often done in parallel with analogous neuropharmacologic and genetic studies of serotonergic neurotransmission in healthy humans and in patients with obsessive-compulsive disorder and other anxiety disorders as described in our other project reports. Major studies completed this year helped to clarify neuronal adaptational processes mediated by serotonin receptors in response to repeated administration of selective serotonin-agonists and serotonin reuptake inhibiting antidepressants in rats. In addition, N-Methyl-D-aspartic acid (NMDA) neurons were demonstrated to modulate the development of serotonin receptor adaptational subsensitivity. In order to take advantage of transgenic technology, we have shifted from studies in rats to studies in mice. This year, we documented a role for free radicals in the production of serotonin projection field lesions using transgenic mice with high levels of superoxide dismutase activity. We have also completed the initial characterization of the consequences of a 50% reduction (in +/- mice) and a complete lack of the mouse cell membrane serotonin transporter (in -/- mice) produced by disruption of the gene for this transporter via homologous recombination. The structure of the gene for the mouse serotonin transporter has been elucidated, and the cellular localization and expression of the transporter in mouse brain has been described.